As to the relevant background prior art reference is made to EP 0 079 244 A, EP 0 168 707 A and EP 0 169 410 A. Herein compounds are described which are in part structurally close to certain compounds of the present invention. However, the compounds disclosed therein are either antibiotics having only xcex2-lactamase activity or antibiotics having only bacterial activity.
This invention now relates to novel 2-S/Oxe2x80x94 and S/N formaldehyde acetal derivatives of carbapenem-3-carboxylic acids of the general formula I 
wherein R1 denotes hydrogen, hydroxymethyl or 1-hydroxyethyl, R2 denotes hydrogen or methyl and R3 denotes a pharmaceutically acceptable group which is bonded to the remaining part of the molecule by an oxygen-carbon single bond or a nitrogen-carbon single bond and which is selected from the group comprising substituted or unsubstituted: alkoxy, alkenyloxy, alkinyloxy, cycloalkoxy, N-heterocyclyl, heterocyclyloxy, heterocyclylcarbonyloxy, heterocyclylthiocarbonyloxy, acyloxy, thioacyloxy, alkoxycarbonyloxy, carbamoyloxy, thiocarbamoyloxy, heterocyclyloxycarbonyloxy, heterocyclyloxythiocarbonyloxy, N-heterocyclycarbamoyloxy, N-heterocyclylthiocarbamoyloxy, heterocyclylcarbonylamino, heterocyclylthiocarbonylamino, heterocyclyloxycarbonylamino, acylamino, alkoxycarbonylamino, alkoxythiocarbonylamino, thioacyclamino, N-heterocyclylcarbamoylamino, N-heterocyclylthiocarbamoylamino, carbamoylamino, thiocarbamoylaymino, imidoylamino, guanidino, N-heterocyclyl-alkoxycarbonylamino, N-heterocyclyl-alkylthiocarbonylamino and N-sulfonylamino where the foregoing alkyl, alkenyl, alkinyl, acyl, thioacyl or imidoyl molecule parts contain 1 to 6 carbon atoms and the heterocyclyl moiety is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen and where the substituents of the above-mentioned groups R may be: alkyl, acyl, thioacyl, heterocyclyl, hydroxyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, amidinoalkoxy, guanidinoalkoxy, acyloxy, heterocyclyloxy, alkylheterocyclyloxy, hydroxyalkylheterocyclyloxy, aminoalkylheterocyclyloxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, carbamoyloxy, alkylcarbamoyloxy, dialkylcarbamoyloxy, thiocarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, thiocarbamoyloxy, alkylthiocarbamoyloxy, dialkylthiocarbamoyloxy, mercapto, alkylthio, hydroxyalkylthio, aminoalkylthio, monoalkylaminoalkylthio, dialkylaminoalkylthio, amidinoalkylthio, acylthio, heterocyclylthio, alkylheterocyclylthio, hydroxyalkylheterocyclylthio, aminoalkylheterocyclylthio, carbamoylthio, monoalkylcarbamoylthio, dialkylcarbamoylthio, thiocarbamoylthio, alkylthiocarbamoylthio, dialkylcarbamoylthio, amino, monoalkylamino, hydroxyalkylamino, aminoalkylamino, dialkylamino, oxo, oximino, or alkylimino, imidoylamino, alkylimidoylamino, dialkylimidoylamino, trialkylammonium, cycloalkylamino, heterocyclylamino, alkylheterocyclylamino, heterocyclylcarbonylamino, alkylheterocyclylcarbonylamino, acylamino, amidino, monoalkylamidino, dialkylamidino, guanidino, alkylguanidino, dialkylguanidino, carbamoylamino, thiocarbamoylamino, alkylcarbamoylamino, thiocarbamoylamino, alkylthiocarbamoylamino, nitro, chloro, bromo, fluoro, iodo, azido, cyano, alkylsulphinyl, alkylsulphonyl, sulphonamido, sulphamoyloxy, alkylsulphamoyloxy, alkylsulphonyloxy or sulpho, sulphoxy, carboxamido, N-monoalkylcarboxamido, N,N-dialkylcarboxamido or carboxy, where the substituents, independently of one another, occur once or several times and their alkyl moiety contains 1 to 6 carbon atoms, and where the heterocyclic moiety is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen, which compounds and their pharmaceutically acceptable salts, esters and amide derivatives are useful as antibiotics and as xcex2-lactamase inhibitors.
Pharmaceutically acceptable groups R3, which are bonded via an oxygen-carbon single bond or a nitrogen-carbon single bond are groups as are customary, for example, in the field xcex2-lactam antibiotics or xcex2-lactamase inhibitors. Such groups are found, for example, in M. S. Sassiver, A. Lewis in xe2x80x9cAdvances in Applied Microbiologyxe2x80x9d, Ed. D. Perlman, Academic Press N.Y. (1970) or in many patents, e. g. U.S. Pat. No. 5,096,899.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein and in the claims, includes non-toxic acid and base salts and the salts of zwitterionic species. Salts with a base include inorganic salts such as sodium, potassium, magnesium and calcium, or ammonium and salts with non-toxic amines such as trialkylamines, alkanolamines, arginine or cyclic amines such as piperazine, procaine and other amines, which have been used to form salts of carboxylic acids. Salts with an acid include inorganic acid salts such as hydrochloride, sulfate, phosphate and the like and organic acid salts such as acetate, maleate, citrate, succinate, ascorbate, lactate, fumarate, tartrate and oxalate and other organic salts with acids which have been used to form salts with amines.
The pharmaceutically acceptable esters and amide derivatives as used herein, serve as prodrugs by being hydrolyzed in the body to yield the antibiotic per se. They are preferably administered orally since hydrolysis occurs principally under the influence of the digestive enzymes. Parenteral administration may be used in some instances where hydrolysis occurs in the blood. Examples of pharmaceutically acceptable esters and amide derivatives include physiologically hydrolyzable esters and amides known and used in the penicillin and cephalosporin fields as, e. g. in Advances in Drug Res. 17, 197 (1988). Such esters and amide derivatives are prepared by conventional techniques known in the art.
The compounds according to the invention have several asymmetric centers and can thus exist in in several stereochemical forms. The invention includes the mixture of isomers and the individual stereoisomers. The most preferred compounds of formula I have the 1R, 5S and 6S configuration of the substituted carbapenem nucleus and the 1xe2x80x2R or the 1xe2x80x2S configuration of the 6-(1-hydroxyethyl) side chain.
Additionally, asymmetric carbon atoms can be included in the substituent R3. The invention includes the compounds having the R and S configuration in the substituent R3.
This invention also relates to processes for the preparation of compounds (I), pharmaceutical compositions comprising such compounds and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
The terminology for compounds of this class may either be based upon the root name xe2x80x9ccarbapenemxe2x80x9d which employs a trivial and simple system of nomenclature (used in the general description). Alternatively, these compounds can also be described by the nomenclature according to the Chemical Abstract system (bicyclo-nomenclature) which is more appropriate to describe individual compounds of this family. Therefore the Chemical Abstract nomenclature is used within the Example Section. 
The classical xcex2-lactam antibiotics such as the penicillins or the cephalosporins have partly become ineffective in the therapy of infectious diseases because of bacterial resistance. Besides the natural resistance of certain bacteria, many strains of pathogenic microorganisms have acquired resistance with continuous use of antibiotics on a large scale. Thus, most species of Staphylococcus aureus have become resistant against the penicillins and many Gram-negative bacteria such as Enterobacter cloacae, Pseudomonas aeruginosa or even Escherichia coli have acquired resistance against the cephalosporins.
Consequently, there is a continuing need for new antibiotics. This search is particularly acute for antibiotics which have a wide spectrum or are orally active.
Within the xcex2-lactams, the carbapenems represent the most effective class of compounds. These are active also against most penicillin- and cephalosporin resistant strains. However, the carbapenems currently used, are administered parenterally because they do not have sufficient oral activity. The lack of oral activity is known in the art and decribed, e. g in Infection 14, (1986), suppl. 2, S 115.
It is an objective of the present invention to provide a novel class of carbapenem antibiotics having a very broad antibacterial spectrum and being orally active.
The compounds of the above formula I are conveniently prepared in accordance with the following equation: 
Thus, the intermediate 3 is prepared by reaction of the starting material 1, containing a leaving group X, wherein R1 and R2 are defined as above-mentioned, with a HS/O- or a HS/N-formaldehyde acetal HSxe2x80x94CH2xe2x80x94R3, preferably in presence of a base, wherein R3 is defined as above-mentioned.
Because of the high reactivity of the HS/O- or HS/N-formaldehyde acetals, especially in presence of a base, the leaving group of X is not very critical. In fact, the reaction can be carried out by using a great variety of leaving groups X. Examples for such leaving groups X are alkoxy groups such as methoxy, alkylsulfonyloxy or arylsulfonyloxy groups such as methylsulfonyloxy, trifluormethylsulfonyloxy and p-toluenesulfonyloxy or dialkoxyphosphinoyloxy or or diaryloxyphosphinoyloxy groups such as dimethoxyphosphinoyloxy or preferably diphenoxylphosphinoyloxy.
Examples for the preparation of starting materials 1 are described in Heterocycles 1984, 21, 29-40, or in Tetrahedron Lett. 1980, 21, 4221-4224.
Inorganic or organic bases can be used in the process 1xe2x86x923, for example potassium or caesium carbonate or tertiary amines such as triethylamine and pyridine or preferably hindered bases such as diisopropylethylamine and 2,6-dimethylpyridine. Because of the high reactivity of the above-mentioned HS/O- or HS/N-formaldehyde acetals the reaction temperature can be varied within a large range. Preferably the process 1xe2x86x9243 is carried out between xe2x88x9270xc2x0 C and room temperature. A unpolar or polar solvent such as methylene chloride or acetonitrile, or preferably N,N-dimethylformamide, is suitable. The process 1xe2x86x923 can also be carried out using phase transfer conditions, for example those using water, an unpolar solvent such as carbon tetrachloride or methylene chloride and a phase transfer catalyst such as tetrabutylammonium bromide.
The process 1xe2x86x923 can also be carried out by using a preformed salt, preferably an alkali, earth alkali or tetraalkylammonium salt of the HS/O- or HS/N- formaldehyde acetals 2. With the inorganic salts, the process 1xe2x86x923 is preferably carried out without additional base in a polar solvent, for example N,N-dimethylformamide. With the more soluble tetraalkylammonium salts, a less polar solvent such as tetrahydrofuran is preferable.
The protecting groups Y in the starting material 1 and in the intermediate 3 are easily removable radicals which are known per se, as are usually used for the purpose in organic synthesis. Protecting groups of this type are found, for example in Gunda I. Georg xe2x80x9cThe Organic Chemistry of xcex2-Lactamsxe2x80x9d, VCH Publishers UK, Cambridge, 1993, pp. 23-29.
Within the deprotection process 3xe2x86x92l, the free carboxylic acid or the corresponding inorganic salts are generated. In special cases it is possible that a selected substituent R3 can be altered simultaneously during the process 3xe2x86x92l.
An example for such special processes is the simultaneous reduction of a 2- azidoethoxy group R3 to a 2-aminoethoxy group during the deprotection of 3 (Y=p-nitrobenzyl) by a catalytic hydrogenolysis.
A prerequisite for the preparation of the compounds of structural formula I was the availability of the corresponding HS/O- and HS/N-formaldehyde acetals 2. We found that the classes of simple HS/O formaldehyde acetals (R3=unsubstituted alkoxy) and HS/N-formaldehyde acetals (R3=unsubstituted acylamino), were not known by prior art. Therefore it was also an object of the present invention to prepare the suitable novel formaldehyde derivatives 2.
2-Alkoxyalkylthiocarbapenems have been reported in EP 0 010 317. They were prepared from known unsubstituted 2-alkoxyalkanethiols as reagents. However, the 2- alkoxymethylthiocarbapenems were not accessible by this method since the required reagents, the HS/O formaldehyde acetals (2, R3 =unsubstituted alkoxy) having 1 to 6 carbon atoms in their alkoxy molecular part, was a class of compounds, unknown by prior art. This class of reagents was considered to be too unstable to be of practical value (Houben-Weyl, Methoden der Org. Chemie., Vol. E 14a/1, G. Thieme ed., Stuttgart, N.Y. 1991, p. 793. This report constitutes a prejudice against the above-mentioned 2-alkoxymethanethiols and against the inventive solution leading to 2-alkoxymethylthiocarbapenem-3-carboxylic acids.
Although a compound with b.p. 52xc2x0 C./20 mbar (15 mm) has been erroneously reported as methoxymethanethiol in the early literature (Chem. Zentralbl. 1912, 1192) we found no later reports of any use of this reagent in Chem. Abstr. Methoxymethanethiol was not accessible using the reported procedure, but had to be prepared on an entirely different (4xe2x86x926xe2x86x922 or 5xe2x86x926xe2x86x922) route. In fact, true methoxymethanethiol is by far more volatile than the reported compound and has a b.p. of 51xc2x0 C. at ambient pressure! As the corresponding HS/O formaldehyde acetals were not accessible, 2- alkoxymethylthiocarbapenems I (R3 methoxy) were never prepared and therefore not described in Chem. Abstr.
Similarly, the unsubstituted HS/N formaldehyde acetals 2 (R3=unsubstituted acylamino) represented an unknown class of compounds. As reagents 2 (R3=acylamino) are required in the preparation of acylaminomethylthiocarbapenems I (R3=acylamino), the latter were not accessible by prior art either. Consequently, 2- acylaminomethylthiocarbapenems have not been described in Chem. Abstr.
The novel HSIO- or HS/N- formaldehyde acetals 2 are conveniently prepared via the following routes: 
wherein R3 is described as above-mentioned. The starting compounds 4 and 5 are known and can be prepared according to procedures known per se or are commercially available, as for example in the case of chloromethyl methyl ether (4, R3xe2x95x90OCH3) or N-hydroxymethylacetamide (5, R3xe2x95x90HNxe2x80x94COxe2x80x94CH3). The process 4xe2x86x926 is preferably carried out in a polar or unpolar solvent such as acetonitrile, ether or chloroform at xe2x88x9270xc2x0 C. to room temperature, the process 5xe2x86x926 can also be carried out in a solvent, or preferably, without a solvent (using an excess of thioacetic acid) at xe2x88x9230xc2x0 C. to +60xc2x0 C. Alternatively, instead of commercially available potassium thioacetate, other alkali or earth alkali thioacetates can be used.
The hydrolysis process 6xe2x86x922 can be carried out using alkaline or acidic conditions, for example using alkali or earth alkali hydroxides or alkali or earth alkali alkoxides, preferably sodium hydroxide or sodium methoxide in a polar solvent such as water, acetonitrile or methyl alcohol. Suitable acidic conditions in the process 6xe2x86x922 use strong acids, preferably hydrogen chloride, in a polar solvent such as water or methyl alcohol. The hydrolyses are preferably carried out at xe2x88x9230xc2x0 C. to room temperature. The HS/O- or HS/N formaldehyde acetals 2 can be isolated in their free state or as alkali, earth alkali or tetraalkylammonium salts.
As already mentioned, currently used carbapenems do not possess sufficient oral activity. The oral activity of the compounds 1, according to the invention, arises from the novel S/O or S/N formaldehyde acetal groups. Similar derivatives of formaldehyde, i.e. an O/O formaldehyde acetal led to increased oral absorbability with the penicillins, for example with pivaloyloxymethyl esters of penicillins as described in Merck Index, 11th ed. 7484, p. 1193. The strong influence of spacer length of substituents was reported in the field of cephalosporins (Journ. Antibiot. 1993, 46, 177), where oral bioavailability has become a target of intensive research. In this literature report, a S/S formaldehyde acetal derivative was found to be superior over fourteen other compounds. Unfortunately, because of the unpolar character of the S/S acetal moiety, the activity against Pseudomonas aeruginosa, inherent in the class of aminothiazol cephalosporins, was largely reduced.
In the field of carbapenems, oral activity was also reported with 2-S/S formaldehyde acetal derivatives in Eur Pat. Appl. 0 481 511 A2, illustrating that the methylene group is suitable as a spacer between two sulfur atoms, to provide oral activity within this family of antibiotics.
However, no reports about S/O- or N/O formaldehyde acetals have appeared and no data about their oral bioavailability or their antibacterial activity have become known. Compared to the above-mentioned, reported 2-S/S-formaldehyde acetals, the compounds I, according to the invention, are more polar and therefore also active against the clinically important pathogen Pseudomonas aeruginosa.
Compared to other reported 2-alkoxyalkylthiocarbapenems, or 2- acylaminoalkylthiocarbapenems, having larger spacer lengths of their alkylene moiety, the compounds I are strongly preferred because of their oral absorbability.
In the general description of the present invention, the group R1 denotes hydrogen, hydroxymethyl or 1-hydroxyethyl, R2 denotes hydrogen or methyl and R3 denotes a pharmaceutically acceptable group, which is bonded to the remaining part of the molecule by an oxygen-carbon single bond or a nitrogen-carbon single bond and which is selected from the group comprising substituted or unsubstituted: alkoxy, alkenyloxy, alkinyloxy, cycloalkoxy, N-heterocyclyl, heterocyclyloxy, heterocyclylcarbonyloxy, heterocyclylthiocarbonyloxy, acyloxy, thioacyloxy, alkoxycarbonyloxy, carbamoyloxy, thiocarbamoyloxy, heterocyclyloxycarbonyloxy, heterocyclyloxythiocarbonyloxy, N-heterocyclycarbamoyloxy, N-heterocyclylthiocarbamoyloxy, heterocyclylcarbonylamino, heterocyclylthiocarbonylamino, heterocyclyloxycarbonylamino, acyclamino, alkoxycarbonylamino, alkoxythiocarbonylamino, thioacylamino, N-heterocyclylcarbamoylamino, N-heterocyclylthiocarbamoylamino, carbamoylamino, thiocarbamoylamino, imidoylamino, guanidino, N-heterocyclyl-alkoxycarbonylamino, N-heterocyclyl-alkylthiocarbonylamino and N-sulfonylamino where the foregoing alkyl, alkenyl, alkinyl, acyl, thioacyl or imidoyl molecule parts contain 1 to 6 carbon atoms and the heterocyclyl moiety is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen and where the substituents of the above-mentioned groups R may be: alkyl, acyl, thioacyl, heterocyclyl, hydroxyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, amidinoalkoxy, guanidinoalkoxy, acyloxy, heterocyclyloxy, alkylheterocyclyloxy, hydroxyalkylheterocyclyloxy, aminoalkylheterocyclyloxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, carbamoyloxy, alkylcarbamoyloxy, dialkylcarbamoyloxy,thiocarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, thiocarbamoyloxy, alkylthiocarbamoyloxy, dialkylthiocarbamoyloxy, mercapto, alkylthio, hydroxyalkylthio, aminoalkylthio, monoalkylaminoalkylthio, dialkylaminoalkylthio, amidinoalkylthio, acylthio, heterocyclylthio, alkylheterocyclylthio, hydroxyalkylheterocyclylthio, aminoalkylheterocyclylthio, carbamoylthio, monoalkylcarbamoylthio, dialkylcarbamoylthio, thiocarbamoylthio, alkylthiocarbamoylthio, dialkylcarbamoylthio, amino, monoalkylamino, hydroxyalkylamino, aminoalkylamino, dialkylamino, oxo, oximino, or alkylimino, imidoylamino, alkylimidoylamino, dialkylimidoylamino, tetraalkylammonium, cycloalkylamino, heterocyclylamino, alkylheterocyclylamino, heterocyclylcarbonylamino, alkylheterocyclylcarbonylamino, acylamino, amidino, monoalkylamidino, dialkylamidino, guanidino, alkylguanidino, dialkylguanidino, carbamoylamino, thiocarbamoylamino, alkylcarbamoylamino, thiocarbamoylamino, alkylthiocarbamoylamino, nitro, chlorine, bromine, fluorine, iodine, azido, cyano, alkylsulphinyl, alkylsulphonyl, sulphonamido, sulphamoyloxy, alkylsulphamoyloxy, alkylsulphonyloxy or sulpho, sulphoxy, carboxamido, N-monoalkylcarboxamido, N,N-dialkylcarboxamido or carboxy, where the substituents, independently of one another, occur once or several times and their alkyl moiety contains 1 to 6 carbon atoms, and where the heterocyclic moiety is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen.
A preferred class of compounds I is that, in which R1 denotes hydrogen, hydroxymethyl or 1-hydroxyethyl, R2 denotes hydrogen or methyl and R3 denotes substituted or unsubstituted alkoxy, heterocyclyloxy, acyloxy, carbamoyloxy, N-heterocyclyl, acylamino, carbamoylamino, imidoylamino where the foregoing alkyl, acyl, thioacyl, or imidoyl molecule parts contain 1 to 3 carbon atoms and the heterocyclyl moiety is monocyclic and contains 3 to 6 ring atoms, of which one or more are selected from the series comprising : oxygen, sulphur and nitrogen and where the substituents of the above-mentioned groups R may be: alkyl, acyl, thioacyl, heterocyclyl, hydroxyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, amidinoalkoxy, guanidinoalkoxy, acyloxy, heterocyclyloxy, alkylheterocyclyloxy, hydroxyalkylheterocyclyloxy, aminoalkylheterocyclyloxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, carbamoyloxy, alkylcarbamoyloxy, dialkylcarbamoyloxy, thiocarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl thiocarbamoyloxy, alkylthiocarbamoyloxy, dialkylthiocarbamoyloxy, mercapto, alkylthio, hydroxyalkylthio, aminoalkylthio, monoalkylaminoalkylthio, dialkylaminoalkylthio, amidinoalkylthio, acylthio, heterocyclylthio, alkylheterocyclylthio, hydroxyalkylheterocyclylthio, aminoalkylheterocyclylthio, carbamoylthio, monoalkylcarbamoylthio, dialkylcarbamoylthio, thiocarbamoylthio, alkylthiocarbamoylthio, dialkylcarbamoylthio, amino, monoalkylamino, hydroxyalkylamino, aminoalkylamino, dialkylamino, oxo, oximino, or alkylimino, imidoylamino, alkylimidoylamino, dialkylimidoylamino, tetraalkylammonium, cycloalkylamino, heterocyclylamino, alkylheterocyclylamino, heterocyclylcarbonylamino, alkylheterocyclylcarbonylamino, acylamino, amidino, monoalkylamidino, dialkylamidino, guanidino, alkylguanidino, dialkylguanidino, carbamoylamino, thiocarbamoylamino, alkylcarbamoylamino, thiocarbamoylamino, alkylthiocarbamoylamino, nitro, chlorine, bromine, fluorine, iodine, azido, cyano, alkylsulphinyl, alkylsulphonyl, sulphonamido, sulphamoyloxy, alkylsulphamoyloxy, alkylsulphonyloxy or sulpho, sulphoxy, carboxamido, N-monoalkylcarboxamido, N,N-dialkylcarboxamido or carboxy, where the substituents, independently of one another, occur once or several times and their alkyl moiety contains 1 to 6 carbon atoms, and where the heterocyclic moiety is monocyclic and contains 3 to 6ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen.
An especially preferred class of compounds I, according to the invention, is the one, in which R1 denotes 1-hydoxyethyl, R2 denotes methyl and R3 denotes substituted alkoxy, acylamino, alkylcarbamoylamino, alkoxycarbamoylamino, N-heterocyclyl and imidoylamino, where the foregoing alkyl, acyl or imidoyl molecule parts contain 1 to 3 carbon atoms and the heterocyclyl moiety is monocyclic and contains 3 to 6 ring atoms, of which one or more are selected from the series comprising: oxygen, sulphur and nitrogen and where the substituents of the above-mentioned groups R3 are basic groups such as amino, alkylamino, dialkylamino, imidoyl, amidino and guanidino. In this case the compounds I according to the invention are very polar and can exist in their zwitterionic form. Therefore such compounds are especially active against Gram-negative bacteria including Pseudomonas aeruginosa.
A selection of compounds I according to the invention showed high antibacterial acivity in the disc susceptibility test after application of 10 micrograms with the following inhibition diameters: Staph. aureus (9-39 mm), E. coli (27-34 mm), E. cloacae (23-27 mm) and Ps. aeruginosa (13-26 mm). These data correspond to those of a clinically useful injectable carbapenem as described in Journ. Antimicrob. Chemotherapy 24, (1989), Suppl. A, 253.
Therefore these new antibiotics are active against a range of bacterial pathogens, which representatively include both gram-positive and gram-negative bacteria such as Staphylococcus aureus, Escherichia coli, Enterobacter cloacae Enterococcus and Pseudomonas aeruginosa. 
Surprisingly, we found that the compounds according to the invention strongly inhibited bacterial xcex2-lactamases isolated from Enterobacter cloacae and Escherichia coli. Moreover, all tested ceftazidime resistant Gram-negative pathogens became susceptible to a combination of ceftazidime and the compounds according to the invention. Thus, these compounds are also very potent xcex2-lactamase inhibitors. The very high activity as xcex2-lactamase inhibitors of the compounds I according to the invention was also observed with isolated bacterial enzymes in the nitrocefin test (R. Reimer, Methodicum Chimicum: Antibiotics, Vitamins and Hormons; F. Korte, M. Goto, eds., Thieme, Stuttgart, 1977, p.11, E. Wasielewski, Arzneimittel, Vol. 4; Chemotherapeutica, Part 1, Verlag Chemie, Weinheim 1972).
A representative of the compounds I according to the invention showed high blood levels in mice after oral treatment with 25 mg per kg, showing the oral absorbability.
Therefore the present invention has the objective of providing a new class of carbapenem antibiotics and xcex2-lactamase inhibitors, which is important in veterinary and human therapy and in inanimate systems. The high and broad spectrum antibacterial activity and xcex2-lactamase inhibition potency of the compounds according to the invention, in combination with their oral activity, could not be expected to this extent from the prior art.
The new compounds according to the invention are valuable antimicrobial substances which are active against most Gram-positive and Gram-negative pathogens including also most penicillin- and cephalosporin resistant and anaerobic bacteria. The free acid and in particular the alkaline and earth metal salts or the zwitterionic species are useful bactericides and can be empolyed to remove pathogens from dental and medical equipment for removing microorganisms and for therapeutic use in humans and animals. For this latter purpose, pharmaceutically acceptable salts as are known per se and are used in the administration of penicillins and cephalosporins, are used. These salts can be used together with pharmaceutically acceptable liquid and solid excipients to form suitable dose unit forms such as pills, tablets, capsules, suppositories, syrups, elixirs and the like, which can be prepared by processes which are known per se.
The new compounds are valuable antibiotics against most pathogenic bacteria and, accordingly, are used in human and veterinary medicine. They can be used as antibacterial medicaments for treating infections caused by Gram-positive and Gram-negative bacteria, for example by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa, Enterobacter cloacae, Enterococcus, Pseudomonas aeruginosa and Bacterium proteus. 
The antibacterial agents can furthermore be used as additives for animal feeds, for preserving foodstuffs or feeds and as desinfectants. For example, they can be used in aqueous preparations in concentrations in the range 0.1 to 100 parts of antibiotic/million parts of solution for destroying and inhibiting the growth of harmful bacteria on medical equipment and as bactericides in industrial applications, for example in water-based paints and in soft water for paper mills, for inhibiting the growth of harmful bacteria.
The products according to the invention may be used alone or together with other active components in any of a large number of pharmaceutical preparations. These preparations can be used in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They can be administered orally, intravenously or intramuscularly.
The preparations are preferably administered in a form which is suitable for absorption through the gastrointestinal tract. Tablets and capsules for oral administration may be in dose unit form and can contain customary medicament excipients, such as binders, for example syrup, gum arabic, gelatin, sorbitol or polyvinylpyrrolidone, fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine, lubricants, for example magnesium stearate, talc, polyethylene glycol or silica, disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by processes which are known per se. Oral liquid preparations can be in the form of of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs and the like or can exist as dry product, for example for reconstitution before using water or other suitable excipients. Liquid preparations of this type can contain additives which are known per se, such as suspending agents, for example sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible oils, for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid. Suppositories contain suppository bases which are known per se, for example cocoa butter or other glycerides.
The preparations for injection can be in dose unit form in ampoules or in containers containing several doses along with an added preservative. The preparations can be in the form of suspensions, solutions or emulsions in oily or aqueous excipients, and they may contain formulation agents such as suspending agents, stabilizers and/or dispersants. Alternatively, the active component may be in powder form for reconstitution before using a suitable excipient, for example sterile, pyrogen-free water.
The preparations can also be in suitable form for absorption through the muscous membranes of the nose and of the throat or of the bronchial tissue, and can be in the form of powders or liquid sprays or inhalants, sucking sweets, as throat paints, etc. For eye and ear medications, the preparations can be used in the form of individual capsules in liquid or semi-solid form or they can be used as drops, etc. Topical applications can exist or be formulated in hydrophobic vehicles as ointments, creams, lotions, paints, powders, etc.
The preparations according to the invention can contain, in addition to the excipient, other components such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity control agents or flavours or the like.
The preparations according to the invention may also contain, in addition to the excipient, enzyme inhibitors, e.g. cilastatin (Merck Index, 11th ed. 2275) to increase the therapeutic effect.
In addition, the preparations may contain one or more active antibacterial components to obtain a broader antibiotic range. Examples for such other active components are antibiotics, preferably xcex2-lactam antibiotics, e.g. penicillins such as Ampicillin or Amoxycillin or cephalosporins such as Cephalexin, Cefachlor or Ceftazidime. With such added conventional xcex2-lactam antibiotics, the active component according to the invention, acts as an antibacterial and as an inhibitor of bacterial xcex2-lactamases.
For veterinary medicine, the preparations can be formulated, for example, as an intramammary preparation in either long-acting or rapid-release vehicles. The dose to be administered is highly dependent on the state of the subject to be treated and the weight of the host, and on the method and frequency of administration. In general, a daily oral dose contains about 10 to about 200 mg of active component/kg of body weight of the subject in case of one or more administrations per day. A preferred daily dose for adult humans is in the range of about 20 to 120 mg of active componentl/kg of body weight.
The preparations according to the invention can be administered in various unit dose forms, for example in solid or liquid dose forms which can be taken orally. The preparations can contain 0.1 to 99% of active material per unit dose, either in solid or in liquid form. The preferred range is about 10 to 60%. The preparations generally contain 15 to about 1500 mg of active component but it is generally preferred to use a dose amount in the range about 250 to 1000 mg. In the case of parenteral administration, the unit dose is normally the pure compound in a sterile water solution or in the form of a soluble powder, which may be dissolved.
The examples below illustrate the products, processes, preparations and methods of treatment according to the invention.